Human liver transplantation.

^hen Welch (1955) reported his first experimental 'yer transplants in dogs, he wrote "it is interesting to ^Peculate about the possibilites of transplanting the ^Uman liver in part or as a whole. The two problems donation and technique of operation seem by themSelves to be insurmountable obstacles with our preSent knowledge. Nevertheless, if some kind of assisance from a donor liver were available to patients in IVer failure it would serve a most useful purpose." ? uuic u vvuuiu oci c iiiuoi

^hen Welch (1955) reported his first experimental 'yer transplants in dogs, he wrote "it is interesting to ^Peculate about the possibilites of transplanting the ^Uman liver in part or as a whole. The two problems donation and technique of operation seem by them-Selves to be insurmountable obstacles with our pre-Sent knowledge. Nevertheless, if some kind of assisance from a donor liver were available to patients in IVer failure it would serve a most useful purpose." ? auuic u vvuuiu oci vc a iiiuoi The technique he described was that of auxiliary 6terotopic transplantation, leaving the recipient liver ? situ and using the homograft as an extra liver.
ut>sequently, Moore et al., (1959), and Starzl et  ?Pic transplantation, removing the animal's own liver replacing it by the donor organ. They found that |n the animals surviving for more than a few days reaction of the homograft occurred, and in later publi-?ations, Starzl et al., (1961Starzl et al., ( ), (1964, described the lstological appearances associated with this. l was thought that liver homotransplantation might ,ave clinical application in certain cases of primary ePatoma or carcinoma of the biliary tract, cirrhotic catients with failing liver function and infants with r?ngenital biliary atresia. The number of such potential ^cipients in England and Wales has been estimated , aPproximately 600 per year, Terblanche and Riddell ^67). Human liver transplantation, however, was not r?ssible until methods of suppressing the rejection Action became available. The drugs azathioprine and ^dnisone were first used in renal transplantation and o own to be of value in this respect in the latter part 1962, andin March 1963 Starzl, in Denver, performed j ? first human liver transplant, Starzl (1963). In the c '?wing six years a total of 79 liver transplants were -p^rr'ed out in various centres throughout the world. n^re are several reason why liver transplantation has livSradvanced so rapidly, the chief one being that the t6 's much more susceptible to ischaemia at body Perature than the kidney. Whereas the liver suffers severe irreversible damage after 15 to 20 minutes following the death of the donor, the kidney is able to withstand up to 2 hours of warm ischaemia, White et al. (1968). The difficulties of obtaining viable organs and preserving function are therefore much increased in liver transplantation. In addition, the technical problems of the operation are considerably greater, and lastly, there is no method comparable to renal dialysis to support failing liver function in patients before and after transplantation.
An outline of the results of human liver transplantation will be given and then the problems that have been encountered will be discussed.

AUXILIARY HETEROTOPIC TRANSPLANTATION
The theoretical advantages of this procedure were considered to be that it would avoid the time consuming and frequently difficult operation of hepatectomy in the recipient, and that any residual function possessed by the recipient liver might be of assistance in the early post-operative period if homograft function was impaired. It has been attempted in 24 patients with non-malignant liver disease, the majority with congenital biliary atresia and a few with cirrhosis, but the results have been very discouraging. The longest surviving patient lived 34 days, and only 3 patients lived longer than 3 weeks. The theoretical advantages were outweighed by technical difficulties in achieving a satisfactory blood supply to the homograft, and the effects of abdominal overcrowding. Further research into this procedure is being carried out, as it would probably have the widest clinical application if the problems mentioned could be solved.

ORTHOTOPIC TRANSPLANTATION
Fifty-five orthotopic transplants have been performed. The majority of the patients had malignant hepatoma or congenital biliary atresia. The early cases were disappointing in that none of the nine patients lived beyond 23 days. Subsequently, however, improvements in the quality of the homografts used, better methods of liver preservation and control of immunosuppression led to more encouraging results.
The first long term survival was achieved in July, 1967, Starzl et al., (1968a. Since that time 46 patients have been treated by transplantation. Twenty-two survived for one month, 7 for 6 months and 5 for more than a year. The longest and most fully documented series of orthotopic liver transplants have been from Denver, Starzl et al? (1963), (1968a), (1968b), (1969), and from the combined team at Addenbrooke's Hospital, Cambridge, and King's College Hospital, London, Calne and Williams (1968), Williams et al., (1969), Calne (1969).
The Denver series consisted of 25 patients. Twelve were infants with congenital biliary atresia, and 7 of them survived for more than 2 months. Four of these however died within 6 months from the complication of septic hepatic infarction, which will be discussed later, and three lived for over a year. Eleven patients received transplants for malignant hepatoma and there were 4 survivors for periods of 4\ to 14? months. All 4 patients, however, developed recurrence of their primary disease. Two cirrhotic patients both died soon after transplantation.
The overall survival in this series was: Number of months after transplant: 1 2 3 6 9 12 Number of patients remaining alive: 13 11 10 7 6 5 In July 1969 there were 3 long term survivors still alive after transplantation for biliary atresia at 12, 14, and months. However, two of these patients were jaundiced due to chronic rejection of the fiomograft.
Calne and Williams reported 12 orthotopic transplants. Seven of these patients had malignant disease of the liver or biliary tract. There were 3 patients with cirrhosis, one with subacute hepatic necrosis and one with congenital biliary atresia. Eight patients survived the immediate postoperative period, and five were able to leave hospital. Six patients subsequently died at 6 days and 3, 7, 10, 11 and 19 weeks post-operatively. 1 from rejection, 2 from pneumonia and 2 from biliary tract complications. Two patients are now alive and well 10 and 11 months after transplantation-for cirrhosis and hepatoma, Williams (1970, Personal communication).
Many factors have affected the outcome of these procedures, but the main ones have been the quality of homograft used, technical difficulties at the time of operation, the rejection reaction and the complications of immunosuppressive drugs, and lastly, recurrence of malignant disease.

THE QUALITY OF THE HOMOGRAFT
Liver function becomes irreversibly damaged if the organ remains at body temperature without a recirculation for more than 15 to 20 minutes. If the organ is rapidly cooled within this time, satisfactory function can be preserved provided it it revascularised in the recipient within 2 or 3 hours. The liver may have been subjected to a period of warm ischaemia before the death of the donor, depending on the mode of death and the duration of any preceding hypotension. One of the main causes of failure following the early human liver transplants was the use of homografts that had undergone ischaemic damage before death of the donor, during prolonged agonal hypotensive periods. The recipients, in these cases, developed liver failure postoperatively. The ensuing bleeding diathesis caused the death of one patient, and made haemostasis extremely difficult to achieve in the others. In later cases, when donor selection was more discriminating and methods of liver preservation had been improved, the homograft function was satisfactory.
The most suitable donors are patients for whon1 resuscitation has been attempted by mechanical ventilation and other means of support, but in whom it is eventually decided to abandon efforts at resuscitation because of irreversible brain damage, irrespective of any transplant considerations. In such circumstances, there is sufficient time available to make the many arrangements necessary before transplantation. Following cessation of heart beat and spontaneous respf' ation in such cases, the period of warm ischaemia is kept to a minimum, either by external cardiac compreS' sion followed by rapid infusion of a cold balance^ electrolyte solution via the portal vein, or the use extracorporeal 'hypothermic perfusion of the cadaver-Preservation of function after the initial cooling of the liver, was achieved in Calne's cases by infusing a physiological conservation medium into the liver, and keeping the organ at 4 degrees Centigrade. This metho" described by Schalm (1968) has been shown experi* mentally to maintain liver function for 3 to 4 hours, buj in human transplants, Calne (1969), the total period of "cold ischaemia" has not exceeded 2 to 3 hours-A more complicated, but more efficient method has been used in the majority of the last 18 transplants in Denver. These homografts were stored for periods up to 3J hours in isolation, but a technique combining hypothermic perfusion and hyperbaric oxygenation Brettschneider et al., (1968). The maximum interv2 from donor death to revascularisation of the hortf?' graft was 7\ hours, and the recipient lived for over a year.

TECHNICAL COMPLICATIONS
The most serious hazards arose in connection with the vascular anastomoses, and the biliary draina9e of the homograft. Vascular complications were parties larly common in cases of congenital biliary atresia, due to the extremely small calibre of the hepatic arterie5' and the increased incidence of anatomical anom3lie of the hilar vessels.
Four such infants in the Derive series died soon after operation, 3 from hepatic arter' occlusion and 1 from portal vein thrombosis. The development of fatal septic hepatic infarction in f?u more infants was largely due to kinking and thrombos' of the right branch of the hepatic artery produced ^ rotation of the liver postoperatively, Starzl (1968b)-' subsequent cases, this complication was prevented anchoring the liver to the diaphragm. Only one ad1* in the Cambridge series developed hepatic arte'" thrombosis.

?
The profound changes in blood coagulation asso ' ated with orthotopic liver transplantation have not on? led to difficulty in achieving haemostasis in son1 cases, especially when a poorly functioning homoQ^ was transplanted, but may also have contributed to incidence of vascular thrombosis in other case Studies by von Kaulla (1966), Blecher (1958), anr Pechet (1959), suggested that increased intravascu coagulation occurred associated with secondary fibrl' olysis. Flute (1969) also found evidence of intravasc lar coagulation following human liver transplantatio ' and emphasised the possible importance of this in j ' production of vascular occusion, especially follo^' the use of antifibrinolytic drugs.
.. The presence of anatomical anomalies of the ho^ graft biliary tract resulted in the death of 2 of Sta rzl'5 Patients from iatrogenically produced biliary obstruction. The technique of biliary drainage used has varied, theoretically, preservation of the sphincter of Oddi is Preferable to prevent ascending cholangitis, but in 'hree of five cases where end to end anastomosis of {he common bile duct was performed, with T tube splint-a9e, biliary fistulae developed, Calne (1969). Calne f?iind anastomosis of the homograft gallbladder to the recipient common bile duct gave better results. This Method, however, is not applicable to cases of biliary atresia. Starzl used cholecystoduodenostomy, and the lrioidence of cholangitis was very low.
Ejection and immunosuppression !t appeared from the early experimental work on liver ^?motransplantation in dogs that the rejection process ^as marked in the majority of cases. It was later found hat in the pig this process was very mild, and that ?n9 term survival was possible without the use of lrr|niunosuppressive drugs, Peacock and Terblanche (1967). it was suggested that the presence of hepalc vein sphincters in the dog, causing outflow block and ischaemic damage, may have accentuated the reaction process seen in this animal. Neither the pig ,'Ver nor the human liver possess these sphincters, and I| was therefore felt that rejection in human liver ?mografts might also prove to be relatively mild, 'rnmunosuppressive drugs have been used in all ex-^ePt one case following human liver transplantation. In instance they were withheld for fear of flaring up a Vlr^l hepatitis. The patient developed acute homo-^aft rejection 4 days post-operatively, and died 2 ^aVs later, Williams et al., (1969). Homograft rejection as seen in the majority of the other patients, but was Modified by drug therapy. In some cases the onset this process was early, within a month of operation, ut in others it was delayed for 2 to 6 months, ^he early rejection episodes in the Cambridge ^ries were controlled toy a temporary increase in the r?se of predmsone. Starzl described three types of early .Section. The mildest form was not accompanied by aUndice. In others the onset was so abrupt and the ^Vrnptoms and signs were so marked that they were ^rnied rejection crises. It was found, however, that ?*h these types of rejection reversed spontaneously, 'thout increasing the dose of 'immunosuppressive ru9s, and that the severity of the rejection crises did Preclude long term survival. The third variety was Solent in nature, and proved to be difficult or imr* ssible to reverse. One patient received a second ansplant because of progressive indolent rejection. I Chronic homograft rejection resembled the early j Solent type except that it was later in onset. All s 6 Patients surviving for prolonged periods in Starzl's 6rie$ were affected, and in only one case was the ^rocess reversible. Although liver function slowly ^enorated, the chronically rejecting homograft sup-,0rted life for many months, and 3 patients survived r; ?ver a year. The development of indolent or chronic k. ption appeared to be related to difficulty in main-TJn'n9 immunosuppressive therapy in these patients. a 6V all received antilymphocyte globulin (iAjLjG.) in q^ion to prednisone and azathioprine. The advantage ^AL.'G. was that it allowed a smaller dose of azathiole'ne to be used, and hence reduced the risk of ^Openia. A serious disadvantage, however, was the development of anaphylactic or local reaction to the foreign protein, which made it impossible to continue the injection in many cases. Indolent or chronic rejection frequently occurred when the drug was stopped. The most satisfactory case in the whole series was the only one in which it was possible to continue long term treatment with AJL.G. It therefore seemed from Starzl's experience that AJL.G. was valuable in controlling the rejection process, but that a state of dependence developed. By contrast, only 3 patients in the Cambridge series were given lA.'L.G. in addition to the other two drugs, for short periods up to 3 weeks, and no signficant advantage was found. Neither of the 2 patients, who are now alive and well 10 and 11 months after transplantation, received it. Chronic rejection was seen in only one case in this series, and could not be reversed despite massive doses of drugs. In this instance, the donor-recipient tissue match was poor.
No association could be found, in the Denver series, between the degree of donor?recipient histo-compatibility as judged by tissue typing, and the patterns of rejection observed, Terasaki (1969). The variations in immunosuppressive therapy played a large part in determining the outcome even when the best tissue match was obtained. A significant correlation has, however, been found between histo-compatibility matching and survival following cadaveric renal transplantation, van Rood (1969), and it is likely that this will also apply in the case of liver transplantation.
The major disadvantage of non-specific immunosuppressive therapy is an increased susceptibility of the patients to infection, and this has been an important cause of morbidity and 'mortality following liver transplantation. The patients were very prone to chest infections and localised sepsis tended to spread rapidly. The responsibile organisims were frequently Gram negative bacilli and fungi, and the infection often followed broad spectrum antibiotic therapy. Starzl found that when the quality of the homograft transplanted was improved, the incidence of infective complications was reduced. Intermittent bacteraemia was found in some patients at various times after operation in both the Cambridge and Denver series. Williams et al., (1969) found the organisms were frequently the same as those isolated in the bile, but there was no evidence of cholangitis or liver infarction, and antibiotics were not given. Starzl (1969a) felt from his experience, that patients were particularly prone to infection after liver transplantation, and postulated that a deficiency of the " bacterial filtering" functions of the liver allowed access of gastrointestinal organisms to the circulation.

RECURRENCE OF DISEASE AFTER LIVER TRANSPLANTATION
All 4 patients in Starzl's series who survived for prolonged periods after transplantation for malignant hepatoma, developed recurrence of their primary disease. Pulmonary metastases were diagnosed in 3 cases on chest X-rays between 4 and 13 weeks postoperatively, and the rate of tumour growth appeared to be very rapid. In all cases recurrence of the tumour involved the homografts, and in one case replaced virtually the whole of it. These results were very disappointing, although not completely unexpected in view of the highly malignant nature of these tumours, the prognosis in most cases being less than 6 months from the time of diagnosis, Lawrence et al., (1966). The original tumours were very large, and microscopic spread of malignant cells must have occurred pre-operative^. Starzl (1969b) commented that the rate of recurrence may have been accelerated by the use of immunosuppressive drugs. iHowever, one of Calne's patients remains alive and well 11 months after transplantation for hepatoma, and liver biopsy now shows essentially normal histology, Williams (1970, Personal communication).

CONCLUSIONS
The high morbidity and mortality associated with liver transplantation is not surprising in view of the poor state of health of many of the recipients pre-operative^, and the numerous problems that have been encountered. Technical calamities and the use of unsuitable donor organs accounted for over half of the mortality in the Denver series. Nevertheless, in a number of patients, symptoms have been relieved and 5 patients have survived for a year or more. Two others are alive and leading reasonably normal lives 10 and 11 months after operation.
Each of the 3 groups of potential recipients present particular problems. In congenital biliary atresia these are the technical difficulties with the vascular anastomoses and the shortage of suitably small sized donor organs. Whether patients with malignant hepatoma, where the disease is still localised to the liver, but beyond the scope of conventional surgery, should still be considered for transplantation in view of the results so far, is debatable. It may be that if patients with less advanced tumours than the ones in Starzl's series were treated, that the results would be better. It appears to be essential to remove the tumour completely if there is to be any hope of avoiding recurrence. Carcinoma of the extrahepatic ducts is a more slowly growing tumour, and although it does not produce symptoms till late, spread beyond the liver and regional lymph nodes is rare. The less malignant nature of this tumour might make it more suitable for transplant surgery than hepatoma.
Cirrhotic patients with failing liver function form the largest group of potential recipients in this country. Terblanche and Riddell (1967) estimated the number to be about 300 per year in England and Wales. The prognosis of the "better risk" cirrhotic patient is difficult to predict with absolute certainty, and there is therefore reluctance to undertake transplantation until the patient is in a terminal state. At present, there is no method of maintaining failing liver function until a suitable donor organ becomes available. If the problems associated with auxiliary liver transplantation can be overcome, this procedure would be particularly applicable to the cirrhotic patient with a small shrunken liver and long standing abdominal distension due to ascites.
Further advances in methods of immunosuppression and organ storage are required before the full potential value of liver transplantation can be realised. The present methods of immunosuppression, although useful, are far from ideal because of their many side effects. A less toxic form of antilymphocyte globulin is required before its full value can be assessed. Some objective way of measuring the degree of rejection, and the effect of immunosuppressive drugs on it, would be extremely useful. The ultimate aim in organ transplantation is the development of methods of inducinS donor specific tolerance in the recipient.
The development of a transportable storage unit. capable of preserving liver function longer than 8 to 12 hours, would greatly facilitate the organisation of liver transplantation. This would allow a donor organ to be used for the most suitable recipient, as judged by tissue typing, and enable a planned procedure rather than " an emergency " operation to be carried out at the centre best equipped for transplantation-In these circumstances, it would obviously be valuable to have some means of assessing the viability of the homograft before transplanting it. It will be some whi'3 before all these objectives are realised.
It has been shown in the centres with the most ex* perience, that even with the techniques at present available, prolonged survival can be achieved in about a fifth of the patients. It would therefore seem reasonable to offer liver transplantation to selected patients with liver disease, having a prognosis of less than six months. The shortage of donor organs however, |S a major problem as in all forms of cadaveric organ transplantation, and will remain so until satisfactory methods of long term storage have been developed